Intratumor heterogeneity and homologous recombination deficiency of high-grade serous ovarian cancer are associated with prognosis and molecular subtype and change in treatment course

Takaya, Hisamitsu; Sakai, Kazuko; Nishio, Kazuto; Murakami, Kosuke; Mandai, Masaki; Matsumura, Noriomi

doi:10.1016/j.ygyno.2019.11.013

Cited by 32 publications

(28 citation statements)

References 38 publications

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“…In a study by Pennington et al (28) compared to germline BRCA1/2 mutations, somatic BRCA1/2 mutations had a similar positive impact on overall survival (OS) and platinum responsiveness. On the other hand, in recent reports, homologous recombination deficiency has gained in importance, in addition to the BRCA mutations, on the targeted treatment (23,29), chemotherapy (30,31), and prognosis (32,33) in EOC patients.…”

Section: Introductionmentioning

confidence: 99%

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

You

et al. 2020

Front. Oncol.

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Objective: Despite several nationwide cohort studies of germline BRCA1/2 mutations and several small cohort studies of somatic BRCA1/2 mutations in Chinese epithelial ovarian cancer (EOC) patients, little is known about the impact of these findings on survival outcomes in this population. In this study of 172 retrospectively recruited Chinese EOC patients, germline and somatic BRCA1/2 mutations and their value for predicting survival outcomes were evaluated. Methods: Unselected patients who visited the study center from January 1, 2011, to January 1, 2015, were recruited and asked to provide peripheral blood samples for this study if they were pathologically confirmed to have primary EOC. All patients received staging surgeries or debulking surgeries involving systemic platinum-based chemotherapy, and the patients were then followed up to December 1, 2017. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) sections and peripheral blood and sequenced for somatic and germline testing, respectively. The demographic and clinicopathological characteristics of the patients were collected to analyze the distribution of BRCA mutations in subgroups. Survival outcomes were compared among various BRCA mutation statuses using univariate and multivariate models. Results: In 58 (33.7%) patients, 63 variants were identified, including variants of unknown significance (VUS) in 18 patients (10.5%) and pathogenic or likely pathogenic variants in a partially overlapping set of 41 patients (23.8%). Germline BRCA mutations, somatic BRCA mutations, BRCA1 mutations in general, and BRCA2 mutations in general were found in 35 (20.3%), 7 (4.1%), 28 (16.3%), and 13 (7.6%) patients, respectively. Five recurrent mutations were identified. Personal and family cancer histories as well as hereditary breast and ovarian cancer (HBOC) criteria were associated with deleterious BRCA mutations both overall and in the germline specifically, whereas only age at diagnosis of EOC was associated with somatic BRCA mutations. In univariate and Cox regression analyses, patients with BRCA1/2 mutations in general had significant improvements in progression-free survival (PFS) and overall survival (OS). You et al. Germline and Somatic BRCA1/2 Mutations in EOC Conclusions: In Chinese EOC patients, the distributions and risk factors associated with germline and somatic BRCA1/2 mutations were similar to those previously reported in international studies. Deleterious BRCA mutations in general were associated with improved survival outcomes in this cohort.

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Section: Introductionmentioning

confidence: 99%

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

You

et al. 2020

Front. Oncol.

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“…Of the remaining 46 studies, 25 were excluded using the exclusion criteria. In the end, 21 studies were included (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). These studies contain 38 pieces of comparison information that were extracted.…”

Section: Resultsmentioning

confidence: 99%

“…The main ITH evaluation method is to calculate variant allele fraction (VAF) based on SNVs and small indel information. Some researchers (18,19,23,30,34) use VAF to calculate the number of clones by clone detection methods such as PyClone and EXPANDS. Other researchers (20,22,24,25,28,31,33,35) directly use VAF to directly reflect the information of ITH through methods such as mutant-allele tumor heterogeneity (MATH).…”

Section: Different Ith Assessment Methods Had Limited Influence On This Studymentioning

confidence: 99%

Intratumor Heterogeneity as a Prognostic Factor in Solid Tumors: A Systematic Review and Meta-Analysis

Gào

Zheng

et al. 2021

Front. Oncol.

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BackgroundThe landscape of intratumor heterogeneity (ITH) is present from the tumor evolution. ITH is a promising clinical indicator, but the association between ITH and prognosis remains controversial. Therefore, a meta-analysis was performed to explore whether ITH can serve as a valuable prognostic indicator in solid tumors.MethodsAll included studies were from PubMed, Embase, Cochrane, and Web of Science databases up to October 10, 2020. Studies based on ITH with available prognostic information were included. Three researchers independently completed study selection and data extraction following PRISMA guidelines. The random-effect model was used for synthesis. Hazard ratio (HR) and 95% confidence intervals (CI) were used with the endpoint defined by overall survival (OS), disease-specific survival (DFS), and progression-free survival (PFS).ResultsA total of 9,804 solid tumor patients from 21 studies were included. Analysis of specific cancers in the TCGA database showed similar results based on different ITH assessment methods, which provided the logical support for data consolidation. Available evidence revealed a negative relationship between ITH and prognosis for a specific cancer (such as lung cancer). However, the OS results from 14 tumor types showed that high ITH associated with shorter survival time [HR 1.65 (95% CI, 1.42–1.91)]. PFS and DFS analyses showed similar results [HR 1.89 (95% CI, 1.41–2.54) and HR 1.87 (95% CI, 1.15–3.04)] in general. The status of tumor metastasis and sampling models were not the confounding factors.ConclusionsHigh ITH is associated with worse prognosis in many solid tumors in general although this association was absent for some cancers. ITH is expected to be a promising clinical prognostic factor for the improvement of assessment, treatment, and surveillance strategy.

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“…The genetic heterogeneity of HGSC has been described previously [12][13][14]. In 66% of cases, HGSC occurs bilaterally and often synchronously, affecting both ovaries; whether they are independent primary tumors from multifocal oncogenesis, arising spontaneously from a similar genetic background, clonally related due to tumorigenesis initiating from one ovary and then metastasizing to the contralateral ovary, or two metastases, has also been evaluated [15].…”

Section: Discussionmentioning

confidence: 99%

Intratumoral Genomic Heterogeneity May Hinder Precision Medicine Strategies in Patients with Serous Ovarian Carcinoma

et al. 2020

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Precision medicine, which includes comprehensive genome sequencing, is a potential therapeutic option for treating high-grade serous carcinoma (HGSC). However, HGSC is a heterogeneous tumor at the architectural, cellular, and molecular levels. Intratumoral molecular heterogeneity currently limits the precision of medical strategies based on the gene mutation status. This study was carried out to analyze the presence of 160 cancer-related genetic alterations in three tissue regions with different pathological features in a patient with HGSC. The patient exhibited histological heterogeneous features with different degrees of large atypical cells and desmoplastic reactions. TP53 mutation, ERBB2 and KRAS amplification, and WT1, CDH1, and KDM6A loss were detected as actionable gene alterations. Interestingly, the ERBB2 and KRAS amplification status gradually changed according to the region examined. The difference was consistent with the differences in pathological features. Our results demonstrate the need for sampling of the appropriate tissue region showing progression of pathological features for molecular analysis to solve issues related to tumor heterogeneity prior to developing precision oncology strategies.

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Intratumor heterogeneity and homologous recombination deficiency of high-grade serous ovarian cancer are associated with prognosis and molecular subtype and change in treatment course

Cited by 32 publications

References 38 publications

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer

Intratumor Heterogeneity as a Prognostic Factor in Solid Tumors: A Systematic Review and Meta-Analysis

Intratumoral Genomic Heterogeneity May Hinder Precision Medicine Strategies in Patients with Serous Ovarian Carcinoma

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